Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.Cl.[OH:26][C:27]1[C:28]([N+]([O-])=O)=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=[O:31]>C1COCC1.O>[OH:26][C:27]1[CH:28]=[C:29]([C:32]([N+:1]([O-:4])=[O:2])=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=[O:31]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [La+3]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C=O)cc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.5 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (15.2 g, 0.1 mol) obtained in the same manner as in Reference Example 3 was dissolved in THF (150 ml), to which sodium nitrate (8.5 g, 0.1 mol) and lanthanum nitrate hexahydrate (8.7 g, 0.2 mol) were added, and then a mixture of concentrated hydrochloric acid and water at a ratio of 1:1 (70 ml) was added dropwise over a period of 20 minutes. The mixture was stirred for 40 minutes at room temperature, and the separated organic layer was successively washed with water (50 ml), a saturated aqueous solution of sodium hydrogencarbonate (50 ml), and a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure to give a mixture of the title compounds 4a and 4b as pale red crystals (4a:4b=1:1, 13.3 g, yield 67.5%) (Table 2).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH:27]([CH3:29])[N:26]([C:30](=[O:32])[CH3:31])[CH:25]([CH3:33])[CH2:24]4)[CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)C.C1COCC1.[OH-].[Li+]>CO.O>[C:30]([N:26]1[CH:25]([CH3:33])[CH2:24][N:23]([C:19]2[CH:18]=[C:17]([N:14]3[CH:15]=[N:16][C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=4)=[N:13]3)[CH:22]=[CH:21][N:20]=2)[CH2:28][CH:27]1[CH3:29])(=[O:32])[CH3:31]
Reactant: CCOC(=O)c1ccc(Nc2ncn(-c3ccnc(N4CC(C)N(C(C)=O)C(C)C4)c3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(C(=O)O)cc4)n3)ccn2)CC1C
Temperature: 60 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
To a solution of 16 g of 4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-benzoic acid ethyl ester (34.5 mMol, 1.00 equiv) in 200 mL of 1:1 MeOH:THF was added 5.75 g of lithium hydroxide (137 mMol, 4.00 equiv) in 100 mL of water. The solution was stirred at 60° C. for 12 hr and then the MeOH and THF were removed via rotary evaporation. The basic solution was neutralized by the addition of 68 mL of 2N HCl and the precipitate was isolated by filtration, yielding 12.5 g of 4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-benzoic acid (28.7 mMol 83.5% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) ∂ 10.215 (1H, s), 9.48 (1H, s), 8.18 (1H, d), 7.91 (2 h, d), 7.71 (2H, d), 7.49 (1H, s), 7.35 (1H, d), 4.38 (2H, m), 3.31 (4H, m), 2.10 (3H, s), 1.22 (6H, m) ppm. LC/MS: 2.02 min/436.30 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=O)[CH3:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([CH3:12])[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cn2nc(Cl)ccc2n1
Temperature: 150 °C
Yield: 80.1 %

Procedure:
To a solution of 6-chloropyridazin-3-amine (2.35 g, 18.1 mmol, 1.0 equiv) in ethanol (15 mL) was added 1-chloropropan-2-one (2.92 mL, 36.3 mmol, 2.0 equiv) and triethylamine (2.53 mL, 18.1 mmol, 1.0 equiv). The solution was heated at 150° C. for 30 min then quenched with water. Purification by column chromatography using 30% ethyl acetate in hexanes elution gave 2.43 g of the brown solid, 80%.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH2:8][CH:9]1[CH2:14][N:13]2[CH2:15][CH2:16][NH:17][CH2:18][CH:12]2[CH2:11][NH:10]1)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:17]1[CH2:16][CH2:15][N:13]2[CH2:14][CH:9]([CH2:8][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:6])[CH3:7])[NH:10][CH2:11][CH:12]2[CH2:18]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)CC1CN2CCNCC2CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN2CC(C[Si](C)(C)C(C)(C)C)NCC2C1

Procedure:
To a solution of the (3R,9aS or 9aR)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]methyl}octahydro-2H-pyrazino[1,2-a]pyrazine (D86, 217 mg) in 9 mL of dichloromethane was added triethylamine (212 μL) and it was brought to −10° C. A solution of acetyl chloride (54 μL) in 2 mL of dichloromethane was added dropwise. After 15 min the reaction was quenched by addition of MeOH. The crude was purified by flash chromatography (silica, CH2Cl2 to CH2Cl2: (0.5 M NH3 in MeOH) 95:5). The sample thus obtained was dissolved in CH2Cl2 and extracted with sat. NaHCO3. The organics were dried and the solvent removed, leading to the title compound (128 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C@H:8]3[CH2:11][CH2:12][NH:13][CH2:14][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)[C@H](C1C=CC=CC=1)O.C([O-])([O-])=O.[Na+].[Na+].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[Br:1][C:2]1[C:10]2[NH:9][C@H:8]3[CH2:11][CH2:12][N:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:14][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1N[C@H]1CCNC[C@@H]21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@@H]2Nc3c(Br)cccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Alternative to the use of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (Compound of Formual 1C) free base, the reaction may also be done by starting with the (S)-mandelate salt of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole. A 100 mL round-bottomed flask is equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, and a N2 inlet on top of the addition funnel. The flask is charged with the S-mandelate starting material (5 g, 12.35 mmol), Na2CO3 (2.88 g, 27.17 mmol), and 25 mL of THF. To the yellow reaction mixture at 25° C. (heating block temperature) is added a solution of ethyl chloroformate (1.64 g, 15.11 mmol) in 5 mL of THF dropwise over ca 70 minutes. The batch is stirred at 25° C. for another 10 min, and is checked by HPLC. Less than 2% of the starting material is observed by HPLC, and the desired product is registered at ca. 98%. To the batch is added 12.5 mL of EtOH, and the batch is concentrated under reduced pressure to remove ca. 30 mL of solvent (mostly THF). To the batch is then added 37.5 mL of H2O, and the resultant mixture shows pH>9 by pH paper. The yellow mixture is then stirred at rt for ca. 1 h, and is filtered. The solid is rinsed with 25 mL of H2O. After drying in a vacuum oven at 58° C. for ca. 16 h, 3.9442 g of a yellow solid is obtained (98% yield). 1H NMR of the solid conformed, and showed no (s)-mandelic acid. HPLC analysis of the product shows the desired product at >99% purity. LC-MS showed a peak with M/e=326 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9](I)[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C[Sn](C)(C)[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1
Reactant: Cc1ccc(-n2c(N)nc3ccccc32)cc1I
Reactant: C[Sn](C)(C)c1ccco1
Product: Cc1ccc(-n2c(N)nc3ccccc32)cc1-c1ccco1

Procedure:
2-Amino-1-[3-(2-furyl)-4-methylphenyl]benzimidazole was prepared from 4-(2-amino-1-benzimidazolyl)-2-iodotoluene and 2-trimethylstannylfuran according to method C. mp 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[F:29])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4ccccc4F)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 521.4(M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18]OS(C)(=O)=O)[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1([CH2:40][CH3:41])[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.[I-].[K+]>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([CH2:18][C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[C:6]3[N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[N:9]=[C:10]([CH3:11])[C:5]=23)[CH2:33][C:32]1([CH2:40][CH3:41])[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1nn(C2CCCCO2)c2nc(Br)cc(COS(C)(=O)=O)c12
Reactant: CCC1(C)CNC(C)(C)CN1C(=O)OC(C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(C)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 41.3 %

Procedure:
A mixture of 130 mg of methanesulfonic acid 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl ester, 99 mg of 2-ethyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester, 0.11 ml of DIPEA and 5 mg of potassium iodide in 2 ml of dry THF was heated to 160° C. for 50 min in a microwave reactor. For workup the mixture was taken up in water and ethyl acetate, the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate). 75 mg (41%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH:16]=[CH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)([CH3:4])[CH3:3].[Cl:28]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)(=O)C.O>[Cl:28][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])[NH:22][CH:21]=1
Reactant: CC(C)(C)NCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NCCOc1ccccc1CCCc1cccc2[nH]cc(Cl)c12
Yield: 74.7 %

Procedure:
A solution of 4.74 g of the product of Example 9 in 43 ml of acetic acid was added with stirring under an inert atmosphere to 2.17 g of N-chlorosuccinimide over 40 minutes and the mixture was diluted with water and iced. The mixture was made alkaline by addition of 32% sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 3.76 g of N-[2-{2-(3-[3-chloro-1H-indol-4-yl]-propyl)-phenoxy}-ethyl]-2-methyl-2-propanamine.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-])=O)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.[H][H]>CCO.[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]2=[O:21]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Reaction time: 1 h
Yield: 77 %

Procedure:
2-Benzyl-5-nitro-2H-isoquinolin-1-one (1.0 g, 3.57 mmol) from step 3 was dissolved in 10 mL of EtOH, and a catalytic amount (50 mg) of 10% palladium on charcoal was added (under N2 atmosphere). The vessel was then closed and exposed to hydrogen at 1 atmosphere for 2 hours. TLC indicated that reduction of the nitro group was complete after 1 hour, and the mixture was filtered and concentrated in vacuo to give 5-amino-2-benzyl-2H-isoquinolin-1-one (0.687 g, 2.75 mmol) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cc(F)cc(F)c2)c(-c2ccccc2)n1
Yield: 47.3 %

Procedure:
6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (160 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,5-difluorophenylboronic acid (0.20 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][C:5]([CH3:9])([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH3:13])[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:18](Cl)Cl>>[CH3:18][O:11][C:10]([C:3]1([CH3:13])[CH2:4][C:5]2([CH3:9])[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2)=[O:12]
Reactant: CC12CCC(C)(C1)C(C)(C(=O)O)C2
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)CC2(C)CCC1(C)C2
Reaction time: 1 h
Yield: 45 %

Procedure:
1,2,4-Trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid (obtained as detailed above) was dissolved in methylene chloride (50 mL), and added dropwise to thionyl chloride (100 mL) at 50° C. After 1 hour, excessive thionyl chloride was distilled out and methanol (100 mL) was added. The reaction mixture was stirred overnight and then poured into saturated aqueous sodium bicarbonate. The resulting mixture was extracted with toluene and the organic phase was distilled to provide 1,2,4-trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (65 g, 45% yield).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O.CC(C)=O>C(O)C>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)[C@H](N)c1ccccc1
Reaction time: 165 h

Procedure:
A solution of ethyl DL-phenylglycinate (5.00 g., 28 mmole) and (+)-tartaric acid (4.18 g., 28 mmole, 1 equiv.) in ethanol (50 ml.) was made at 58°. The solution was cooled, acetone (4.1 ml., 55.6 mmole, 2 equiv.) was added and the mixture was stirred at 20° to 25° for 165 hours. The solid was filtered off, washed with ethanol (2 × 10 ml.) and dried at 26°/2 mm. for 41/2 hours to give ethyl D-phenylglycinate (+)-hemitartrate as a monoethanol solvate (9.338 g., 89%), [α]D -46.5° (c 2.5 H2O).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH:31]([NH2:33])[CH3:32])[CH:28]=[N:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C@@H:31]([C:29]2[CH:28]=[N:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:30]=2)[CH3:32])[N:7]=1)([CH3:15])[CH3:14].[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C@H:31]([C:29]2[CH:28]=[N:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:30]=2)[CH3:32])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: COc1ccc(-n2cc(C(C)N)cn2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2cc([C@@H](C)Nc3nccc(N4C(=O)OC[C@@H]4C(C)C)n3)cn2)cc1
Product: COc1ccc(-n2cc([C@H](C)Nc3nccc(N4C(=O)OC[C@@H]4C(C)C)n3)cn2)cc1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (93 mg, 0.38 mmol), 1-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethanamine hydrochloride (514 mg, 2.03 mmol, 5.3 equiv) and iPr2NEt (0.605 mL, 3.46 mmol, 9.0 equiv) in DMSO (1.5 mL) was heated at 110° C. for 16 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 70%) provided (S)-4-isopropyl-3-(2-((R)-1-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-1-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][Na].[CH3:4][C:5]1([CH3:14])[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7](=O)[CH2:6]1>CC#N>[CH3:12][C:10]1([CH3:13])[CH2:9][C:7]2([CH2:1][O:2]2)[CH2:6][C:5]([CH3:14])([CH3:4])[NH:11]1
Reactant: CO[Na]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: CC#N
Product: CC1(C)CC2(CO2)CC(C)(C)N1

Procedure:
44.55 g (0.825 mole) of CH3ONa were then added, under stirring, to the mixture and then, in half an hour, a solution of 77.5 g (0.5 mole) of triacetonamine dissolved in 50 cc of CH3CN was gradually added. After having stirred the mixture for 4 hours at room temperature, most of the solvent was distilled under vacuum and 500 cc of H2O were added to the mixture.
Reaction SMILES: C1(C[O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([O:35][C:12]1[CH:11]=[C:10]([C:9]([OH:8])=[O:36])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)(=[O:46])[CH3:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OC(C)=O)cc(C(=O)O)c1
Yield: 115.2 %

Procedure:
To a stirred and ice bath cooled solution of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy) benzoic acid phenylmethyl ester in 7.5 ml of methylene chloride and 2.8 ml (0.02 mol) of triethylamine was added 0.86 ml (0.012 mol) of acetyl chloride. The reaction mixture was stirred in an ice bath for 1 hour, at room temperature for 2 hours and then was washed with 1N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to a solid. Trituration with methanol and filtration gave 5.17 g (96% yield, mp 55°-56°) of 3-acetyloxy-5-(octadecyloxy)benzenecarboxylic acid.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20](=O)[CH3:21])[C:15]=2[OH:23])[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:24]([C:26]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([N+:39]([O-:41])=[O:40])[CH:30]=1)=[S:27])[NH2:25]>Cl.O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20](=[N:25][NH:24][C:26]([NH:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([N+:39]([O-:41])=[O:40])[CH:30]=3)=[S:27])[CH3:21])[C:15]=2[OH:23])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.2 %

Procedure:
Dimethylformamide (1 ml) and conc. hydrochloric acid (1 drop) were added to 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (60 mg, 0.21 mmol) synthesized in Synthetic Example 1 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (57 mg, 0.21 mmol) synthesized in Reference Synthetic Example 56, and the mixture was stirred at room temperature for 21 hours. Water was added, and the precipitated solid was filtered, purified with a silica gel column chromatography (n-hexane/ethyl acetate=1/1 then chloroform/methanol=95/5). The obtained solid was extracted with ethyl acetate, washed with a saturated ammonium chloride aqueous solution, saturated sodium chloride aqueous solution. The organic layer was concentrated to obtain the desired product as a pale yellow solid (104 mg, yield 92%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+]>CC(C)=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of 2-bromomethyl-benzonitrile (300 mg, 1.53 mmol) and sodium azide (129 mg, 1.99 mmol) in acetone was stirred overnight at rt. The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (6:1) to give the title compound (212 mg, 88%). MS (DCI/NH3) m/z 176 (M+18)+. 1HNMR (400 MHz, DMSO-d6) δ ppm 4.69 (s, 2H) 7.58 (td, J=7.67, 1.23 Hz, 1H) 7.66 (d, J=7.67 Hz, 1H) 7.76 (td, J=7.67, 1.23 Hz, 1H) 7.91 (dd, J=7.67, 1.53 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:23]2[C:24]([CH3:40])=[C:25]([NH:29]C(=O)OCC4C=CC=CC=4)[CH:26]=[CH:27][CH:28]=2)=[CH:6][N:5]=1)=[CH:15][C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=3)(=[O:3])[NH2:2]>CO.C1COCC1.[Pd]>[NH2:29][C:25]1[C:24]([CH3:40])=[C:23]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-6-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.125 g, 0.233 mmol) and 10% Pd/C (0.025 g, 0.023 mmol) in methanol (8.75 mL) and THF (2.92 mL) was stirred under a hydrogen balloon. After 1 hr, the reaction was flushed with nitrogen, filtered through a pad of CELITE®, rinsed with MeOH. The filtrate was concentrated in vacuo, dissolved in CH2Cl2 (100 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (0.0786 g, 0.196 mmol, 84% yield) as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])(C(O)=O)[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N(P([O:41][C:42]1C=CC=CC=1)(OC1C=CC=CC=1)=O)=[N+]=[N-].C([N:50](C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@:20]([N:50]=[C:42]=[O:41])([CH3:27])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@]1(C(=O)O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@@]1(N=C=O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
To a solution of (1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylic acid, 826, (0.100 g, 0.216 mmol) and (azido(phenoxy)phosphoryl)oxybenzene (0.093 mL, 0.432 mmol) in 10 mL of toluene was added 1 mL of N-ethyl-N-isopropyl-propan-2-amine. The reaction was warmed to reflux overnight. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (EtOAc), yielding 40 mg of desired product as a white foam.